RRC ID 43107
Author Kajiguchi T, Chung EJ, Lee S, Stine A, Kiyoi H, Naoe T, Levis MJ, Neckers L, Trepel JB.
Title FLT3 regulates beta-catenin tyrosine phosphorylation, nuclear localization, and transcriptional activity in acute myeloid leukemia cells.
Journal Leukemia
Abstract Deregulated accumulation of nuclear beta-catenin enhances transcription of beta-catenin target genes and promotes malignant transformation. Recently, acute myeloid leukemia (AML) cells with activating mutations of FMS-like tyrosine kinase-3 (FLT3) were reported to display elevated beta-catenin-dependent nuclear signaling. Tyrosine phosphorylation of beta-catenin has been shown to promote its nuclear localization. Here, we examined the causal relationship between FLT3 activity and beta-catenin nuclear localization. Compared to cells with wild-type FLT3 (FLT3-WT), cells with the FLT3 internal tandem duplication (FLT3-ITD) and tyrosine kinase domain mutation (FLT3-TKD) had elevated levels of tyrosine-phosphorylated beta-catenin. Although beta-catenin was localized mainly in the cytoplasm in FLT3-WT cells, it was primarily nuclear in FLT3-ITD cells. Treatment with FLT3 kinase inhibitors or FLT3 silencing with RNAi decreased beta-catenin tyrosine phosphorylation and nuclear localization. Conversely, treatment of FLT3-WT cells with FLT3 ligand increased tyrosine phosphorylation and nuclear accumulation of beta-catenin. Endogenous beta-catenin co-immunoprecipitated with endogenous activated FLT3, and recombinant activated FLT3 directly phosphorylated recombinant beta-catenin. Finally, FLT3 inhibitor decreased tyrosine phosphorylation of beta-catenin in leukemia cells obtained from FLT3-ITD-positive AML patients. These data demonstrate that FLT3 activation induces beta-catenin tyrosine phosphorylation and nuclear localization, and thus suggest a mechanism for the association of FLT3 activation and beta-catenin oncogeneic signaling in AML.
Volume 21(12)
Pages 2476-84
Published 2007-12
DOI 10.1038/sj.leu.2404923
PII 2404923
PMID 17851558
MeSH Active Transport, Cell Nucleus / physiology* Acute Disease Animals Cell Line, Tumor Gene Expression Regulation, Leukemic* Glycogen Synthase Kinase 3 / antagonists & inhibitors Glycogen Synthase Kinase 3 / physiology Glycogen Synthase Kinase 3 beta Humans Interleukin-3 / pharmacology Leukemia, Myeloid / genetics Leukemia, Myeloid / metabolism* Leukemia, Myeloid / pathology Membrane Proteins / pharmacology Mice Neoplasm Proteins / antagonists & inhibitors Neoplasm Proteins / physiology* Phosphorylation Phosphotyrosine / metabolism Protein Processing, Post-Translational / physiology* RNA, Small Interfering / pharmacology Recombinant Proteins / metabolism Staurosporine / analogs & derivatives Staurosporine / pharmacology Transcription, Genetic / physiology* Tyrphostins / pharmacology beta Catenin / genetics beta Catenin / metabolism* fms-Like Tyrosine Kinase 3 / antagonists & inhibitors fms-Like Tyrosine Kinase 3 / genetics fms-Like Tyrosine Kinase 3 / physiology*
IF 9.944
Times Cited 26
Human and Animal Cells